The advent of highly active antiretroviral therapy (HAART) in the mid-1990s resulted in a dramatic increase in survival of HIV patients. HAART is the current standard of care. Due to the substantial progress that has been made over the past two decades in the development of effective and well tolerated combination antiretroviral regimens, most HIV-1 infected persons who initiate antiretroviral therapy at early stages in the disease process and who are fully adherent to their antiretroviral regimens can anticipate life expectancies that are measured in decades. While combination antiretroviral treatment has changed the face of the HIV epidemic and enabled physicians to provide effective therapy, several issues and limitations of these regimens have emerged. Currently, there are over 30 drugs approved for HIV/AIDS treatment, all of them with common problems, including: drug resistance; side effects with long-term morbidities; incomplete recovery of immune function; drug interactions; and requirement for daily, lifelong adherence.
The most significant limitation of continuous therapy (CT) has been the necessity and challenge of continued daily adherence to the medications. It is known that reduced compliance over years of therapy results in drug resistance and subsequent elimination of treatment options.
Further, undesirable metabolic effects are another concern with HIV treatment. There is evidence of increased myocardial infarction rates among patients on antiretroviral therapy. An important study on this subject was the DAD study (Data Collection on Adverse Events of Anti-HIV Drugs), which found an increased risk of coronary artery disease in people on all types of antiretroviral therapy (Law M, Friis-Moller N, Weber R, et al., Modelling the 3-year risk of myocardial infarction among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study, HIV MED. 2003; 4:1-10). The DAD study also found that some of the risk was lowered upon discontinuation of anti-HIV drugs. Additional metabolic and general side effects of antiretroviral therapy include cardiovascular complications, lipoatrophy, peripheral neuropathy, and accelerated liver disease (Julg B, Goebel F D, Treatment interruption in HIV therapy: a SMART strategy?, INFECTION, 2006; 34:186-188 (“Julg”)).
Further, the potential risks of CT are generally believed to include higher rates of drug side effects, more difficult adherence (and particularly so for significant patient subsets), and potentially more drug resistance resulting in fewer drug options secondary to higher antiretroviral therapy exposure. The high cost of medications related to CT also continues to be problematic.
The availability of an effective, simplified maintenance regimen would be of benefit to a subset of HIV-1 infected persons who are challenged by adherence and/or chronic nucleoside toxicity.
A number of studies have been conducted to evaluate the possibility of treatment simplification following control of viral replication with an induction regimen. Most of these simplification trials have involved the substitution of a boosted HIV-1 protease inhibitor such as lopinavir or darunavir for an effective combination regimen. Although the strategy has been successful in a substantial fraction of those who undergo regimen simplification, the overall body of evidence suggests that boosted protease inhibitor maintenance therapy is generally less effective than maintenance on a three drug regimen. Factors influencing the likelihood of success include the duration of successful suppression prior to the regimen simplification and the extent to which patients are adherent to their simplified regimens. Although it has also been suggested that some patients may fail because of variability in trough concentrations of protease inhibitors, this has not been substantiated in rigorously conducted studies. Other concerns that have been raised include the ability of HIV-1 protease inhibitors to achieve suppressive levels in the central nervous system. The current consensus appears to be that this approach should be reserved for specific patient populations in which considerations related to chronic nucleoside toxicity and/or adherence to complex antiretroviral regimens are dominant. In these situations, the importance of adherence and of close monitoring of plasma HIV-1 RNA levels has been emphasized. In the case of HIV-1 protease inhibitor maintenance therapy, reestablishment of control of retroviral replication has generally been achieved by resumption of combination therapy.
Thus, there is a need for strategies that can optimize the use of available antiretroviral drugs in order to maximize the benefits while minimizing the risks. Treatment substitution (TS), including intermittent therapy (IT), is one way to attempt to optimize antiretroviral therapy. Two main strategies for IT have been studied: time-defined and CD4+ cell-guided. Time-defined strategies involve predetermined treatment interruption, such as medication breaks on weekends and one-month-on/one-month-off scheduling, in an effort to improve quality of life, promote adherence, decrease antiretroviral exposure, and minimize the development of resistance. The CD4+ cell-guided strategy, used in the National Institutes of Health's Strategies for Management of Antiretroviral Therapy (SMART) study, utilized CD4+ cell counts to determine the starting and stopping point of IT. In other words, antiretroviral treatment is started when the CD4+ cell count falls below a certain threshold, stopped when it increases above a certain level, restarted when the CD4+ cell count again falls below the threshold, and so on.
The potential benefits of TS and IT, including fewer side effects, better adherence, and improved overall health and quality of life, may be weighed against potential risks, including the possible increase in the development of resistance, lasting damage to the immune system, and an increase in the risk of HIV transmission due to non-suppression of viral load.
TS/IT Studies
Based on published data from ACTG5197 trial entitled “A Phase II double-blind, randomized, placebo-controlled study to evaluate the antiretroviral effect of immunization with the MRY Ad5 HIV-1 GAG vaccine in HIV-1 infected individuals who interrupt antiretroviral drug therapy” the viral load will increase within 4 weeks after treatment interruption. See Schooley, Robert T. et al., ACTG 5197: A Placebo Controlled Trial of Immunization of HIV-1 Infected Persons with a Replication Deficient Ad5 Vaccine Expressing the HIV-1 Core Protein, J. INFECT. DIS., Sep. 1, 2010, 202(5): 705-716 (“Schooley”). The impact of treatment interruption on the CD4 cell count reduction is also observed after 4 weeks, actually the downward trend in CD4 cell counts can be observed by week 1, as depicted in FIGS. 1-3. This study was conducted in HIV infected men and women of 18 to 55 year old (inclusive), who have maintained viral load suppression for at least 24 months and had a CD4 cell counts of greater than 500 cells/mm3 and HIV-1 RNA<50 copies/mL.
These changes in both viral load and CD4 counts are depicted in FIGS. 1-3. As it is depicted in FIG. 1, if the subjects who have their viral load below 50 copies/mL and their CD4 cell counts>500 cells/mm3 have a treatment interruption, then after 4 weeks approximately 50% of them will have a viral load of >500 copies/mL; and almost 100% of the subjects will have a viral load of >500 copies/mL by 10 weeks. FIG. 2 depicts the actual change in the median viral load and their 95% Confidence Intervals over a period of 16 weeks. After week 3 there is a clear increase in the viral load and by week 6 the viral load reaches the highest level and was maintained through week 16.
As depicted in FIG. 1, in subjects who have CD4 cell count of greater than 500 cells/mm3 and have a treatment interruption, a trend toward a decline in CD4 was observed by week 1. This downward trend in CD4 cell count continued and after 4 weeks of treatment interruption approximately 10%, and by week 16 more than 30%, reduction in their viral load was observed.
Separately, it has been reported that several studies have investigated both CD4+ cell- and time-guided IT strategies (Siegel L, El-Sadr W, New Perspective in HIV Treatment Interruption: The SMART Study, PRN NOTEBOOK, vol. 11, no. 2, October 2006 (“Siegel”)). For example, the Staccato trial randomized 430 patients to CT or IT (Ananworanich J, Gayet-Ageron A, Le Braz M, et al., CD4-guided scheduled treatment interruptions compared to with continuous therapy for patients infected with HIV-1: results of the Staccato randomized trial, LANCET, 2006; 368:459-465). Patients in the IT group started therapy when their CD4+ counts dropped below 350 cells/mm3 and then stopped therapy once their CD4+ counts increased above 350 cells/mm3. This small study showed 5.8% of the IT patients experienced acute retroviral syndrome. Minor manifestations of HIV infection, such as candidiasis and thrombocytopenia, were more common in the IT group, while adverse events, including diarrhea and neuropathy, were more common in the CT group. Ten patients (2.3%) had resistance mutations; there were no differences between groups. There was a 62% savings in antiretroviral therapy costs (Julg).
Additionally, it has been reported that the Window-ANRS 106 trial randomly assigned 403 patients with undetectable viral loads and CD4+ counts greater than or equal to 450 cells/mm3 while on antiretroviral therapy to receive either CT or IT in eight-week off/on cycles. The primary endpoint of CD4+ counts less than 300 cells/mm3 was reached by 3.6% in the IT group, compared with 1.5% in the CT group. At week 96, the proportion of patients with CD4+ counts greater than 450 cells/mm3 and viral loads of 400 copies/mL or less was 75% vs. 92% and 81% vs. 90%, IT or CT, respectively. The IT arm, the investigators concluded, appeared safe and without excess resistance, while reducing antiretroviral exposure by 48.5%.
It has been reported that another study, the ANRS 1269 Trivican trial, randomized 326 patients on antiretrovirals therapy with CD4+ counts greater than 350 cells/mm3 and undetectable viral loads to CT or one of two IT strategies: CD4+ cell-count-guided (stopping at 350 cell/mm3 and restarting at 250 cells/mm3) or time-guided (two-months-off, four-months-on). At an interim point, the CD4+ cell-guided arm was terminated prematurely due to safety concerns. The results demonstrated a two-fold higher serious morbidity rate in the CD4+ cell-guided group, compared with the CT group, with recommendations for future studies to utilize higher CD4 count thresholds.
In yet another study, the ISS PART trial, it has been reported 273 subjects were randomized to one of five different time-guided IT schedules (one to three months off therapy, followed by three months on treatment) or CT, with the primary endpoint being the proportion of patients with CD4+ counts greater than 500 cells/mm3 after 24 months. Significantly more patients in the CT group reached the primary endpoint (86.5% vs. 69.1%; P=0.0075), with similar rates of virological failure.
In connection with the SMART study, results of a two-armed treatment comparison of CT to CD4+ cell-guided IT have also been reported. The goal of the CT arm was to use antiretroviral therapy, irrespective of the CD4+ cell count, to achieve and maintain undetectable viral loads. The goal of the IT arm was to defer therapy until the CD4+ count was below 250 cells/mm3, continue treatment until the CD4+ count increased above 350 cells/mm3, with subsequent stops and restarts using these CD4+ cell count cutoffs. Patients entering the SMART study were required to have a current CD4 count of greater than 350 cells/mm3 (CD4+ count nadir was permitted to be lower). They were randomized 1:1, in an open-label fashion, to either CT or IT. The SMART investigators hoped to enroll 6,000 patients and to accumulate approximately eight years of follow-up data. The primary endpoints were progression to AIDS or death, survival, serious complications (e.g., cardiovascular, renal, and hepatic), serious disease progression events (e.g., disseminated MAC, toxoplasmosis, cryptococcosis, Kaposi's sarcoma), and grade 4 events. Additional comparisons involved adherence, side effects, metabolic complications, quality of life, drug resistance, and cost.
It has been reported that the SMART study was halted on Jan. 11, 2006, due to safety concerns. At that time, 5,472 patients were enrolled and included in an intent-to-treat analysis. In an effort to obtain a comprehensive understanding of the primary outcome, several sub-studies were conducted to assess various outcome measures, including quality of life, risk behavior, body composition and metabolic parameters, neurological complications, and anal dysplasia. The SMART study represents an international effort with participants from 33 countries and 318 sites. The majority of the participants were from North America and the United States with additional participation through sites in Europe, Africa, Asia, and South America. Baseline characteristics of the SMART study groups include a median age of 46 years: 27% were women and 30% were black. The median follow-up time was 14 months, with 2% lost to follow up. The median CD4+ count at entry was approximately 598 cells/mm3, with median nadirs of approximately 251 cells/mm3. Seventy-one percent had viral loads less than 400 copies/mL, 24% had prior clinical AIDS, and 4.7% were antiretroviral naïve.
Reported results of the SMART study demonstrate statistically significant differences in clinical disease progression including death between the two groups. There were 117 events per 100 person-years of follow up in the IT group, compared with 47 events per 100 person-years of follow up in the CT group. This translated into a relative risk of clinical disease progression of 2.5 for the IT arm (P<0.0001). Kaplan-Meier curves demonstrated slow and consistent accumulation of events in both arms over time, but with the IT group showing higher event rates starting four months after randomization. The component breakdown of the primary SMART study endpoint shows that the relative risk favors the CT group with respect to survival and disease progression. Notably, despite greater exposure to antiretroviral therapy, severe cardiovascular, hepatic, and renal complications were unexpectedly lower in the CT group, with a cumulative relative risk of 1.5. When the primary endpoint of HIV disease progression or death was further subdivided by race and sex, the CT group still maintained a clear advantage over the IT arm. The SMART study investigators also subdivided the outcomes by baseline CD4+ cell counts and viral loads, and demonstrated the same advantage to the viral suppression (CT) arm. There were particular safety concerns regarding the group of patients with low CD4+ nadirs. However, the data demonstrated that these patients were no more likely to experience disease progression or death when compared with patients with higher CD4+ nadirs. In fact, all groups of CD4+ nadirs favored the CT group equally. With respect to viral loads at study entry, patients with viral loads less than 400 copies/mL had many more events in the IT arm, while those with detectable HIV-RNA levels did equally well in both arms.
Reports of the SMART study results showed that IT compared with CT, was associated with increased risks of HIV disease progression or death, serious HIV disease progression, and severe complications, and that the results were not affected by gender, race, baseline CD4+ cell count, or nadir CD4+ cell count. Moreover, the risk was determined to be three-fold higher for patients on antiretroviral therapy with baseline viral loads below 400 copies/mL. Based on the SMART study, and other IT studies, it has been conventionally accepted that episodic use of antiretroviral therapy based on CD4+ cell counts, as utilized in the SMART study design, is inferior to continuous antiretroviral therapy for the management of antiretroviral-experienced patients. Further, in contrast to other IT studies that measured only viral load and CD4+ counts, the SMART study is conventionally considered particularly powerful because a broad range of clinical endpoints were examined. In sum, the reported results of SMART study are conventionally believed to discourage IT.
Although PRO 140 would require either subcutaneous (SC) or intravenous (IV) administration, its favorable pharmacokinetics might allow dosing as infrequent as once or twice monthly. The ability to administer the drug infrequently under medical supervision could obviate one of the continuing challenges of close adherence to daily boosted protease inhibitor regimens that appear to be relatively unforgiving in maintenance settings when administered as the sole antiretroviral regimen. This is an open-label pilot study of PRO 140 monotherapy as maintenance therapy for those previously fully suppressed on combination antiretroviral regimens.
HIV-1
Infection of cells by human immunodeficiency virus type I (HIV-1) is mediated by the viral envelope (Env) glycoproteins gp120 and gp41, which are expressed as a noncovalent, oligomeric complex on the surface of virus and virally infected cells. Entry of the virus into target cells proceeds through a cascade of events at the cell surface that include (1) binding of the viral surface glycoprotein gp120 to a cell surface receptor, (2) Env binding to fusion coreceptors, and (3) multiple conformational changes in gp41.
The first high-affinity interaction between the virion and the cell surface is the binding of gp120 to cell surface CD4, which is the primary receptor for HIV-1. This binding induces conformational changes in gp120, which enable it to interact with one of several chemokine receptors. The CC-chemokine receptor 5 (CCR5) is the major co-receptor for macrophage-tropic (R5) strains, and plays a crucial role in the transmission of HIV-1. T cell line-tropic (X4) viruses use CXCR4 to enter target cells, and usually, but not always, emerge late in disease progression or as a consequence of virus propagation in tissue culture. Some primary HIV-1 isolates are dual-tropic (R5X4) since they can use both co-receptors, though not always with the same efficiency. Binding of gp120 to a chemokine receptor in turn triggers conformational changes in the viral transmembrane glycoprotein gp41, which mediates fusion of the viral and cellular membranes. Each stage of this multi-step process can be blocked with inhibitors of the appropriate viral or cellular protein, and the inhibitors of gp120, gp41, CD4 and coreceptor are collectively known as entry inhibitors. Entry inhibitors represent at least 4 distinct classes of agents based on their molecular targets and determinants of viral resistance.
CCR5 as a Target for Anti-HIV-1 Therapy
As first demonstrated in 1986, HIV-1 binds to target cells via the CD4 receptor but requires additional host cell factors to mediate entry. Over the next decade, a number of candidate coreceptors were proposed, but none reproducibly mediated viral entry when coexpressed with CD4 in otherwise nonpermissive cells. However, in 1996, certain chemokine receptors, mainly CCR5 and CXCR4, were shown to serve as requisite fusion coreceptors for HIV-1.
A link between HIV-1 and chemokines are small (about 8 kDa) homologous soluble proteins. Chemokines mediate the recruitment and activation of immune cells. They are classified as CC-, CXC-, CX3C- and XC-chemokines based on the number and sequential relationship of the first two of four conserved cysteine residues; most are either CC- or CXC-chemokines. The CC-chemokines RANTES, MIP-1α and MIP-1β, were shown to block replication of primary macrophage-tropic strains of HIV-1. Using expression cloning techniques, It was discovered that the chemokine receptor fusin (later renamed CXCR4) was a fusion coreceptor for strains of HIV-1 adapted to growth on T cell lines. Shortly thereafter, several groups reported the cloning of CCR5, a CC chemokine receptor with specificity for RANTES, MIP-1α and MIP-1β, and others then demonstrated that CCR5 was the main entry cofactor used by primary macrophage-tropic HIV-1 isolates. The patterns of CCR5 and CXCR4 expression helped solve long-standing riddles concerning the tropism of different strains of HIV-1. Macrophage-tropic, T-cell-line-tropic and dual-tropic viruses could be more descriptively classified as being R5, X4 and R5X4 viruses based on their abilities to utilize CCR5, CXCR4 or both receptors, respectively, for entry.
A variety of other chemokine receptors can function as HIV-1 coreceptors when over-expressed in vitro. The list includes CCR8, Apj, V28, US28, CCR2b, CCR3, gpr1, Bonzo (STRL33, TYMSTR), and BOB (gpr15). Clearly, proteins belonging to the chemokine receptor family have biochemical properties that promote HIV-1 membrane fusion. However, most of the above-mentioned coreceptors are not very efficient, are not normally coexpressed with CD4, and function only with certain strains of HIV-1, HIV-2 or SIV. The in vivo relevance of these alternative coreceptors has not been established.
Several factors make CCR5 an attractive target for new antiretroviral therapies. CCR5 plays a central role in HIV-1 transmission and pathogenesis, and naturally-occurring mutations in CCR5 confer protection from HIV-1 infection and disease progression. The most notable CCR5 polymorphism involves a 32 bp deletion in the coding region of CCR5 (A32). The A32 allele encodes a nonfunctional receptor that fails to reach the cell surface. Individuals who possess one normal and one mutant CCR5 gene express lower levels of CCR5, and their T cells are less susceptible to R5 virus infection in vitro. A32 heterozygotes experience a milder course of disease characterized by reduced viral burdens and delayed progression to AIDS. These results support the concept that reducing CCR5 availability can lower viral replication and slow disease progression.
Individuals with two mutant CCR5 genes comprise a significant fraction of people of northern European descent; the demography is suggestive of a prior pandemic of a CCR5-using pathogen. Such individuals represent human CCR5 “knockouts” in that they do not express a functional CCR5 protein. Except in rare instances, these individuals are resistant to HIV-1 infection, and their T cells cannot be infected with R5 viruses in vitro. These findings underscore the central role of CCR5 in HIV-1 transmission. In fact, it is now known that R5 viruses mediate transmission in nearly all cases and mediate progression to AIDS in most cases.
Importantly, individuals who lack CCR5 enjoy normal health and display no obvious immunologic or other defects. This may reflect the redundancy of chemokine signaling pathways and the rather limited pattern of expression of CCR5. CCR5 expression is largely confined to activated T cells and macrophages, which represent the primary targets for HIV-1 infection in vivo, although low-level CCR5 expression has been reported on other tissues, such as smooth muscle.
CCR5 knockout mice have been generated and provide further insight into the effects of abrogating CCR5 function. CCR5 knockout mice develop normally and are ostensibly healthy, although minor alterations in immune responses can be observed upon challenge with particular pathogens. In contrast, the CXCR4 knockout is a lethal phenotype in mice, and has not been observed in humans.
Taken together, these genetic analyses strongly support a new therapeutic approach based on CCR5 as a drug target. The error-prone nature of reverse transcriptase generates immense genetic diversity that fosters the development of drug-resistant isolates, and HIV-1's ability to utilize multiple fusion coreceptors provides one path to resistance. Drug-resistant viruses have been isolated for all marketed antiretrovirals, which nevertheless provide important therapeutic benefit when used in appropriate combinations. Thus, despite the potential emergence of drug-resistant viruses, CCR5-targeting agents may serve as a new treatment paradigm for HIV-1 infection.
Although the apparent non-essential nature of CCR5 suggests that CCR5 antagonists may be well tolerated in vivo, further studies are required to determine that long-term effects of abrogating CCR5 function in individuals whose immune systems developed in its presence. Such potentially deleterious effects may be mitigated by use of agents that bind to CCR5 and inhibit binding of HIV-1 thereto, but do not impair normal CCR5 function. One agent demonstrated to have such properties is the humanized anti-CCR5 mAb, PRO 140, which effectively blocks HIV-1 replication at concentrations that do not inhibit the physiologic activity of CCR5. PRO 140 was identified using a fluorescence resonance energy transfer (RET) assay screen for anti-HIV activity. It is potently antiviral, having an IC90 of about 4 μg/ml and protects diverse primary target cell types. Repeated administration of PRO 140 led to prolonged control of HIV-1 replication without viral escape in the hu-PBL SCID mouse model.
Subsequent to the identification of the small-molecule CCR5 antagonist, TAK-779, several other small-molecule CCR5 antagonists have been identified. Four of these (SCH-C, SCH-D, UK-427,857, GW873140) have completed similarly designed Phase 1 studies in HIV-infected individuals. Each of these agents mediated dose-dependent about 1 log10 mean reductions in HIV-1 RNA levels during the treatment period of 10-14 days. As expected, viral loads rebounded to baseline levels following cessation of therapy. The most common drug-related side-effects were neurologic (headache, dizziness) and gastrointestinal (nausea, diarrhea, flatulence), and these were not dose limiting. With the exception of SCH-C, none of the above-identified agents induced clinically significant changes in QTc intervals.
A double-blind, placebo-controlled, single oral dose study has also been conducted to evaluate the safety, tolerability, and pharmacokinetics of TAK-652, the successor compound to TAK-779, in healthy male volunteers. The single administration of TAK-652 solution was reportedly safe and well tolerated.
Overall, these studies provide preliminary validation of CCR5 as a target for HIV-1 therapy. While the small-molecule CCR5 antagonists represent patentably distinct chemical series with differing pharmacokinetic and metabolic properties, the compounds share many properties in their inhibition of CCR5 function, binding site on CCR5, resistance profiles, and dosing regimen. These similarities may conceivably limit the number of genuine treatment options afforded by small-molecule CCR5 antagonists. Moreover, it remains to be determined whether there are untoward consequences of chronic blockade of CCR5 function, and the utility of small-molecule CCR5 antagonists for HIV-1 therapy remains to be established by demonstration of appropriate safety and efficacy in Phase 3 clinical studies.
Monoclonal Antibody Therapeutics
In recent years, mAb products have provided new standards of care in diverse disease settings. Currently, several mAbs are approved by the U.S. Food and Drug Administration (FDA) for indications including cancer, autoimmune disease, transplant rejection and viral infection. In many instances, mAbs provide safety, efficacy and ease-of-use profiles that are unrivalled by small-molecule compounds.
The humanized anti-CCR5 mAb, PRO 140, is structurally, functionally and mechanistically distinct from the small-molecule CCR5 antagonists and therefore represents a unique CCR5 inhibitor class. PRO 140 is a humanized version of the murine mAb, PA14, which was generated against CD4+ CCR5+ cells. PRO 140 binds to CCR5 expressed on the surface of a cell, and potently inhibits HIV-1 entry and replication at concentrations that do not affect CCR5 chemokine receptor activity in vitro and in the hu-PBL-SCID mouse model of HIV-1 infection.
Important differences between PRO 140 and small-molecule CCR5 antagonists are summarized in Table 1. It is evident from Table 1 that, whereas small-molecule CCR5 antagonists in development share many properties, PRO 140 is clearly distinct from these small-molecule inhibitors. The differences between the two CCR5 inhibitor classes reveal that PRO 140 may offer a fundamentally distinct, and in many ways complementary, product profile from that of small-molecule CCR5 antagonists. Indeed, PRO 140 represents a novel therapeutic approach to treating HIV-1 infection and could play an important role in HIV-1 therapy irrespective of small-molecule CCR5 antagonists.
TABLE 1Comparison of PRO 140 and small-molecule CCR5 antagonistsSmall MoleculesPRO 140Identification ScreenChemokine BindingHIV-1 EntryBlock Natural Activity ofYesNoCCR5Potential for ImmuneYesNoSuppression/DysregulationCardiac, NeurologicalNo ToxicityTolerabilityToxicities for someBinding site on CCR5Common HydrophobicExtracellularPocket defined byEpitope thatTransmembranespans MultipleRegions of CCR5HydrophilicDomainsViral Cross-ResistanceSignificantLimitedDevelopment of Resistance6 to 19 weeksNone at 40 weeksin VitroDrug-Drug InteractionsSignificantUnlikelyFood InteractionsSignificantUnlikelyDosingOnce or Twice DailyBiweekly toMonthly
PRO 140 is a humanized IgG4,κ monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5), under development as therapy for human immunodeficiency virus (HIV) infection. PRO 140 is directed at an ECL2 domain of the CCR5 cell surface receptor for HIV-1. Binding of this domain of the CCL5 molecule interferes with viral entry by interfering with the final phase of viral binding to the cell surface prior to fusion of the viral and cell membranes. Thus, PRO 140 is a viral-entry inhibitor and belongs to a new class of HIV/AIDS therapeutics that are intended to protect healthy cells from viral infection. PRO 140 is a humanized monoclonal antibody directed against CCR5, a molecular portal that HIV uses to enter cells. Prior to the current TS studies, PRO 140 was the subject of four Phase 1/1b and two Phase 2a clinical trials, each of which demonstrated its ability to significantly reduce HIV viral load in human test subjects infected with HIV. The clinical studies demonstrate that PRO 140 effectively blocks the HIV co-receptor CCR5, and clinical trial results thus far indicate that it does not affect the normal cell function. That is, PRO 140 1) stops HIV replication without blocking immune function, 2) provides prolonged antiviral activity and tolerability, 3) has a different resistance profile compare to any HIV drugs, 4) has no toxicity (unlike all of today's HIV drugs), and 5) is designated as a FDA Fast Track drug candidate. The Phase 1 and 2a Clinical Results (based on data from over 110 patients) shows that PRO 140 provides for rapid viral load suppression better than or as good as any HIV Drug in the market today with one injection. See FIG. 2.
Nucleic acids encoding heavy and light chains of the humanized PRO 140 antibody have been deposited with the ATCC. Specifically, the plasmids designated pVK-HuPR0 140, pVg4-HuPR0140 (mut B+D+I) and pVg4-HuPR0140 HG2, respectively, were deposited pursuant to, and in satisfaction of, the requirements of the Budapest Treaty with the ATCC, Manassas, Va., U.S.A. 20108, on Feb. 22, 2002, under ATCC Accession Nos. PTA 4097, PTA 4099 and PTA 4098, respectively. The American Type Culture Collection (ATCC) is now located at 10801 University Boulevard, Manassas, Va. 20110-2209.
PRO-140 has been administered intravenously or subcutaneously to HIV-1 infected individuals in Phase 1 and Phase 2 studies of safety, tolerability, pharmacokinetics and pharmacodynamics. The drug has been well tolerated following administration of single doses of 0.5 to 5 mg/kg or up to three weekly doses of up to 324 mg. Single subcutaneous doses of 324 mg have resulted in drops in plasma HIV-1 RNA levels of approximately 1.0 log10. Repetitive weekly administration of this dose of PRO 140 has been associated with drops in plasma HIV-1 RNA levels of approximately 1.5 log10. Serum concentrations of PRO 140 above the IC50 for clinical isolates of HIV-1 are maintained for at least 2 weeks following a single dose of 324 mg. Plasma HIV-1 RNA levels rise to baseline levels as PRO 140 is cleared from the plasma and, presumably, other compartments.
The applicant submits that the PRO 140 IgG4 antibody is superior to all of today's HIV therapies in that it has far fewer side effects, much less toxicity, leads to much better patient adherence, and achieves a better viral load drop upon initial administration than any other HIV drug. Thus, the PRO 140 antibody appears to be a powerful antiviral agent leading to potentially fewer side effects and less frequent dosing requirements as compared to daily drug therapies currently in use.